rs309208

Variant names:

• chr18-68680890-T-G
• rs309208
• NM_019022.5:c.1035+91A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_019022.5(TMX3):​c.1035+91A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0135 in 1,307,280 control chromosomes in the GnomAD database, including 1,488 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (850 hom., cov: 32)
  • Exomes 𝑓: 0.0073 (638 hom.)
• Consequence: TMX3 NM_019022.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.03
• Publications: 1 publications found

Genes affected

TMX3 (HGNC:24718): (thioredoxin related transmembrane protein 3) This gene encodes a member of the disulfide isomerase (PDI) family of endoplasmic reticulum (ER) proteins that catalyze protein folding and thiol-disulfide interchange reactions. The canonical protein encoded by this gene has an N-terminal ER-signal sequence, a catalytically active thioredoxin domain, one transmembrane domain and a C-terminal ER-retention sequence. This gene is expressed in many tissues but has its highest expression in heart and skeletal muscle. It is expressed in the retinal neuroepithelium and lens epithelium in the developing murine eye and haploinsufficiency of this gene in humans and zebrafish is associated with microphthalmia. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Apr 2017]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 18-68680890-T-G is Benign according to our data. Variant chr18-68680890-T-G is described in ClinVar as Benign. ClinVar VariationId is 1262037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.197 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019022.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMX3	NM_019022.5	MANE Select	c.1035+91A>C		intron	N/A	NP_061895.3
	TMX3	NM_001350514.2		c.954+91A>C		intron	N/A	NP_001337443.1
	TMX3	NM_001350515.2		c.612+91A>C		intron	N/A	NP_001337444.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMX3	ENST00000299608.7	TSL:1 MANE Select	c.1035+91A>C		intron	N/A	ENSP00000299608.2	Q96JJ7-1
	TMX3	ENST00000564631.5	TSL:1	n.*719+91A>C		intron	N/A	ENSP00000456587.1	H3BVI1
	TMX3	ENST00000915516.1		c.1158+91A>C		intron	N/A	ENSP00000585575.1

Frequencies

GnomAD3 genomes AF: 0.0600 AC: 9121 AN: 152108 Hom.: 843 Cov.: 32

Gnomad AFR AF: 0.200

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0367

Gnomad ASJ AF: 0.00721

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00176

Gnomad OTH AF: 0.0531

GnomAD4 exome AF: 0.00733 AC: 8469 AN: 1155054 Hom.: 638 AF XY: 0.00674 AC XY: 3818 AN XY: 566804

African (AFR) AF: 0.218 AC: 5401 AN: 24782

American (AMR) AF: 0.0183 AC: 398 AN: 21694

Ashkenazi Jewish (ASJ) AF: 0.00820 AC: 144 AN: 17562

East Asian (EAS) AF: 0.00 AC: 0 AN: 32792

South Asian (SAS) AF: 0.000618 AC: 29 AN: 46908

European-Finnish (FIN) AF: 0.0000509 AC: 2 AN: 39286

Middle Eastern (MID) AF: 0.0242 AC: 117 AN: 4836

European-Non Finnish (NFE) AF: 0.00166 AC: 1522 AN: 919148

Other (OTH) AF: 0.0178 AC: 856 AN: 48046

GnomAD4 genome AF: 0.0601 AC: 9142 AN: 152226 Hom.: 850 Cov.: 32 AF XY: 0.0587 AC XY: 4370 AN XY: 74442

African (AFR) AF: 0.200 AC: 8311 AN: 41502

American (AMR) AF: 0.0366 AC: 559 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00721 AC: 25 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4832

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10618

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.00176 AC: 120 AN: 68026

Other (OTH) AF: 0.0526 AC: 111 AN: 2112

Alfa AF: 0.0267 Hom.: 805

Bravo AF: 0.0697

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.3
DANN	Benign	0.73
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs309208; hg19: chr18-66348127;